Cancer is the second most prevalent cause of death in the United States, causing 450,000 deaths per year. While substantial progress has been made in identifying some of the likely environmental and hereditary causes of cancer, there is a need for additional therapeutic modalities that target cancer and related diseases. In particular there is a need for therapeutic methods for treating diseases associated with dysregulated growth/proliferation. Cancer is a complex disease arising after a selection process for cells with acquired functional capabilities like enhanced survival/resistance towards apoptosis and a limitless proliferative potential. Thus, it is preferred to develop drugs for cancer therapy addressing distinct features of established tumors. The PI3K/AKT/mTOR pathway, which is constitutively activated in many types of cancers, is one of the prominent pathway that promote tumor cell survival. Initial activation of the PI3K/AKT/mTOR pathway occurs at the cell membrane, where the signal for pathway activation is propagated through class IA PI3K. Activation of PI3K can occur through tyrosine kinase growth factor receptors (e.g. platelet-derived growth factor receptor (PDGF-R), human epidermal growth factor 1/2/3 receptor (EGFR, HER2/3), or the insulin-like growth factor 1 receptor (IGF-1R)), cell adhesion molecules through integrin-linked kinase (ILK), Ca2+/calmodulin-dependent kinase kinase (CaMKK), nuclear DNA-dependent protein kinase (DNA-PK), G-protein-coupled receptors, and oncogenic proteins, such as Ras. Once PI3K is activated, it catalyzes phosphorylation of the D-3 position on phosphoinositides to generate the biologically-active phosphatidylinositol-3,4,5-triphosphate [PI(3,4,5)P3, PIP3] and phosphatidylinositol-3,4-bisphosphate [PI(3,4)P2, PIP2]. PIP3 binds to the pleckstrin homology (PH) domains of phosphoinositide-dependent kinase 1 (PDK-1), AKT, and other PH-domain containing proteins, such as Rho and PLC. As the consequence of binding to PIP3, the proteins are translocated to the cell membrane and are subsequently activated. The tumour suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) antagonizes PI3K by dephosphorylating PIP3, thereby preventing translocation and activation of PDK1, AKT and other signaling proteins.1,2 
AKT is the major effecter of PI3K, which elicits a broad range of downstream signaling events. It recognizes and phosphorylates the consensus sequence RXRXX(S/T) when surrounded by hydrophobic residues. As this sequence is present in many proteins, about 50 AKT substrates have been identified and validated.3, 4 These substrates control key cellular processes such as apoptosis, cell cycle progression, transcription, and translation, stress adaptation, metabolism, and metastasis of tumor cells. For instance, AKT phosphorylates the FOXO subfamily of forkhead family transcription factors, which inhibits transcription of several pro-apoptotic genes, e.g. Fas-L, IGFBP1 and Bim.5, 6 Additionally, AKT can directly regulate apoptosis by phosphorylating and inactivating pro-apoptotic proteins such as Bad, which control the release of cytochrome c from mitochondria, and apoptosis signal-regulating kinase-1, a mitogen-activated protein kinase kinase involved in stress-induced and cytokine-induced cell death.7 In contrast, AKT can phosphorylate IκB kinase, which indirectly increases the activity of nuclear factor κB and stimulates the transcription of pro-survival genes.8 Cell cycle progression can also be affected at the G1/S transition by AKT through its inhibitory phosphorylation of the cyclin dependent kinase inhibitors, p21WAF1/CIP1 and p27KIP1. In addition AKT can phosphorylate mouse double minute 2 (MDM2) leading to its nuclear translocation and promotion of degradation of p53. This in consequence leads to an decrease in p21Cip1mRNA.9 Furthermore AKT has also an important function in the control of the G2/M transition by e.g. phosphorylation of Myt1 and FOXO3a.10, 11 
The best-studied downstream substrate of AKT is the serine/threonine kinase mTOR. AKT can directly phosphorylate and activate mTOR, as well as cause indirect activation of mTOR by phosphorylating and inactivating TSC2 (tuberous sclerosis complex 2, also called tuberin), which normally inhibits mTOR through the GTP-binding protein Rheb (Ras homolog enriched in brain). When TSC2 is inactivated by phosphorylation, the GTPase Rheb is maintained in its GTP-bound state, allowing for increased activation of mTOR. mTOR exists in two complexes: the TORC1 complex, in which mTOR is bound to Raptor, and the TORC2 complex, in which mTOR is bound to Rictor.12 In the TORC1 complex, mTOR phosphorylates its downstream effectors S6 kinase (S6K1) and 4EBP-1. S6K1 can then phosphorylate its substrate, a ribosomal protein called S6. 4EBP-1, when phosphorylated cannot bind effectively to its binding partner, eIF4E. The cumulative effect is to increase protein translation, especially of highly structured, capped mRNA species.13 Although mTOR is generally considered a downstream substrate of AKT, mTOR in complex with Rictor can also phosphorylate AKT at S473, thereby providing a level of positive feedback on the pathway.14 Finally, S6K1 can also regulate the pathway by catalyzing an inhibitory phosphorylation on insulin receptor substrate proteins (IRS). This prevents IRS from activating PI3K, which indirectly lowers activation of AKT. This feedback pathway is very important for developing PI3K/AKT/mTOR pathway inhibitors, as the re-activation of PI3K has to be taken into consideration during the evaluation of the anti-tumor efficacy of the PI3K pathway inhibitors.15, 16 
In addition to the well described PI3K/AKT/mTOR axis of the PI3K signaling pathway, PI3K, AKT and mTOR also receive and branch differential signaling events that are independent from the axis. For example, mTOR has the crosstalk with and is activated by MAPK pathway through ERK and RSK regulated phosphorylation of TSC2.17 There are collective data describing the AKT/mTOR-independent PI3K-mediated signaling events. First of all, PI3K downstream signaling molecule PDK1 responses to increased levels of PIP3 and activates not only AKT, but also a group of AGC kinases comprising S6K, RSK, SGK and PKC isoforms, which play essential roles in regulating tumor cell growth, proliferation, survival and metabolism.18 Furthermore, many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth. Instead, these cells retain robust PDK1 activation and membrane localization and exhibit dependency on the PDK1 substrate SGK3. SGK3 undergoes PI3K- and PDK1-dependent activation in PIK3CA mutant cancer cells. Thus, PI3K may promote cancer through both AKT-dependent and AKT-independent mechanisms.19 In addition to PDK1 and AGC kinases, PI3Ks regulate also other cancer related signaling proteins such as PLC, Rac, Rho, ITK and BTK, etc.
In humans, class I PI3K has four isoforms of the p110 catalytic subunits, p110α, p110β, p110γ and p110δ. p110α and p110β are present in all cell types, while p110δ and p110γ are highly enriched in leukocytes. p110 subunits are divided into a class IA group (p110α, p110β and p110δ), which bind the p85 regulatory subunit, and a class IB group (p110γ), which does not. The p85 regulatory subunits contain Src homology 2 (SH2) domains and bind phosphorylated tyrosine (pTyr), which lead to the activation of the class IA p110 catalytic subunits. On the other hand, p110γ is activated directly through G protein coupled receptors (GPCRs). Recent data indicated that p110β was also activated by GPCRs directly through Gβγ protein.20 
The signaling inputs to each class I PI3Ks are diverse and well depicted in genetic analyses. Thus, activation of AKT was impaired in p110α-deficient MEFs upon stimulation by classical RTK ligands (EGF, insulin, IGF-1, and PDGF).21 On the other hand, MEFs in which p110β is ablated or replaced by a kinase-dead allele of p110β respond normally to growth factor stimulation via RTKs.22 Instead, p110β catalytic activity is actually required for AKT activation in response to GPCR ligands (such as LPA). As such, p110α appears to carry the majority of the PI3K signal in classic RTK signaling and is responsible for tumor cell growth, proliferation, survival, angiogenesis and metabolism whereas p110β mediates GPCR signaling from mitogens and chemokines and therefore may regulate tumor cell proliferation, metabolism, inflammation and invasion.23, 24 
Although the differences in signaling outputs from the four class I PI3K isoforms are still largely unknown, it seems that PI3Kβ together with PTEN determines the basal levels of PIP3 in tumor cells, while RTK stimulated elevation of PIP3 is controlled mainly by PI3Kα. The potential for differential signaling outputs downstream of specific PI3K isoforms, in parallel with a possibly more universal Akt activation are yet to be discovered.
Activation of PI3K/AKT kinases promotes increased nutrient uptake, converting cells to a glucose-dependent metabolism that redirects lipid precursors and amino acids to anabolic processes that support cell growth and proliferation. These metabolic phenotype with overactivated AKT lead to malignancies that display a metabolic conversion to aerobic glycolysis (the Warburg effect). In that respect the PI3K/AKT pathway is discussed to be central for survival despite unfavourable growth conditions such as glucose depletion or hypoxia.
A further aspect of the activated PI3K/AKT pathway is to protect cells from programmed cell death (“apoptosis”) and is hence considered to transduce a survival signal. By acting as a modulator of anti-apoptotic signalling in tumor cells, the PI3K/AKT pathway, particular PI3K itself is a target for cancer therapy. Activated PI3K/AKT phosphorylates and regulates several targets, e.g. BAD, GSK3 or FKHRL1, that affect different signalling pathways like cell survival, protein synthesis or cell movement. This PI3K/AKT pathway also plays a major part in resistance of tumor cells to conventional anti-cancer therapies. Blocking the PI3K/AKT pathway could therefore simultaneously inhibit the proliferation of tumor cells (e.g. via the inhibition of the metabolic effect) and sensitize towards pro-apoptotic agents. PI3K inhibition selectively sensitized tumor cells to apoptotic stimuli like Trail, Campthothecin and Doxorubicin.
The resistance of many types of cancer to chemo- and targeted therapeutics represents the major hurdle in successful cancer treatment. Cancer cells can escape the effect of most commonly used drugs despite their different chemical structure and intracellular targets. Many mechanisms underlying the failure of therapeutic drugs have been well studied. Activation of PI3K/AKT pathway plays a key role in different cellular functions such as growth, migration, survival and differentiation. Data accumulated in the last decade have established that this pathway plays also a key role in resistance to both chemo-, radiation- and targeted therapeutics. Collective data describing constitutive or residual pathway activation in cells that have developed resistance to conventional chemotherapy and radiation, as well as to other targeted therapies such as EGFR antagonism. For example, experiments in doxorubicin-resistant CML cell lines demonstrated high levels of PI3K/AKT activity; importantly, doxorubicin resistance could be overcome by decreasing PI3K/AKT activity. Further experimental evidence was observed in two pancreatic cancer cell lines in which decreased levels of phosphorylated AKT can increase gemcitabine-induced apoptosis. Synergistic antitumor activity with cisplatin was also demonstrated in xenograft models of lung cancer.
The PI3K/AKT pathway is linked to resistance to both chemo- and targeted therapeutics. The Inhibition of PI3Kβ might present a promising strategy to overcome the resistance to radiation and DNA targeting therapy. Nuclear PI3Kb can induce nuclear AKT phosphorylated on both T308 and S473 in response to either IR or the DNA-damaging agent doxorubicin.
In summary, PI3K plays central role downstream of many cancer related signaling pathways that are critical for tumorigenesis, tumor growth/proliferation and survival, tumor cell adhesion, invation and metastasis, as well as tumor angiogenesis. In addition, gain-function mutation of PIK3CA is common in several human cancers and the link between tumor suppressor gene PTEN and PI3Kβ has been observed in some tumors such as prostate cancer. An increased expression of the p110β and p110δ isoforms has been observed in some colon and bladder tumors, and in glioblastoma. In addition, nuclear PI3K plays roles in DNA synthesis and repair.35 Furthermore, p110δ controls proliferation in acute myeloid leukemia (AML) and migration of breast cancer cells,36 whereas p110γ plays roles in tumor angiogenesis, drug resistance of CML cells, and pancreatic tumor growth and survival.37 Thus, developing PI3K inhibitors for treatment in mono- and combination therapy is a promising strategy to treat cancer and overcome cancer treatment resistance.
Thus inhibitors of PI3K represent valuable compounds that should complement therapeutic options not only as single agents but also in combination with other drugs, e.g. DNA targeting agent and radiation therapy.
Alpharadin (Xofigo) uses alpha radiation from radium-223 decay to kill cancer cells. Alpharadin targets to bone tissue by virtue of its chemical similarity to calcium. It has an effect over a range of 2-10 cells and causes less damage to surrounding healthy tissues compared to current radiation therapy based on beta or gamma radiation. Significant increase in median overall survival was demonstrated in Phase III clinical trials and Alpharadin (Xofigo) was approved as a treatment for castration-resistant prostate cancer (CRPC) patients with symptomatic bone metastases.
Different PI3K inhibitors are disclosed in e.g. WO2008/070150, WO2012/062743, WO2012/062745, WO2012/062748.
However, the state of the art does not disclose the combinations of the present invention comprising an inhibitor of PI3K kinase or a physiologically acceptable salt thereof and a pharmaceutically acceptable salt of the alkaline-earth radionuclide radium-223.
A preferred suitable pharmaceutically acceptable salt of radium-223 is the dichloride (Ra223Cl2).
radium-223 dichloride is a novel, targeted alpha-emitter that selectively binds to areas of increased bone turnover in bone metastases and emits high-energy alpha-particles of extremely short (<100 μm) range.37 
It is the first targeted alpha-emitter approved for the treatment of prostate cancer with bone metastasis.
As a bone-seeking calcium mimetic, radium-223 is bound into newly formed bone stroma, especially within the microenvironment of osteoblastic or sclerotic metastases.38 
The high-energy alpha-particle radiation induces mainly double-strand DNA breaks resulting in a potent and highly localized cytotoxic effect in the target areas containing metastatic cancer cells.39 
The short path length of the alpha-particles also means that toxicity to adjacent healthy tissue and particularly the bone marrow may be reduced.40 
Radium-223 has demonstrated a favorable safety profile, with minimal myelotoxicity, in phase 1 and 2 studies of patients with bone metastases.41 
Phase 2 studies have shown that radium-223 reduces pain, improves disease-related biomarkers (e.g., bone alkaline phosphatase [ALP] and prostate-specific antigen [PSA]), and have suggested a survival benefit in patients with CRPC and bone metastases.42, 43 
The ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer patients) trial provides proof of principle for the role of targeted alpha-emitters in oncology. In this trial, radium-223 significantly prolonged overall survival with a 30.5% reduction in risk of death compared with placebo in patients with CRPC (Castration Resistant Prostate Cancer) and bone metastases. Median survival with radium-223 was longer than placebo by 2.8 months. All main secondary efficacy endpoints were statistically significant and favored treatment with radium-223, including the clinically defined endpoint of time to first skeletal-related event, which was significantly prolonged in patients receiving radium-223.
A substantial percentage of cancer patients is affected by skeletal metastases. As many as 85% of patients with advanced lung, prostate and breast carcinoma develop bony metastases.44 Established treatments such as hormone therapy, chemotherapy and external radiotherapy often causes temporary responses, but ultimately most bone cancer patients experience relapses.45 There is thus a strong need for new therapies to relieve pain and slow down tumor progression.
223Ra is used as an α-emitting radiopharmaceutical for targeting of calcified tissues, e.g., bone surfaces and osseous tumor lesions. It can be suitable as a bone seeking radiopharmaceutical.
It thus may be used for prophylactic cancer treatment by delivering a focused dose to bone surfaces in patients with a high probability of having undetected micrometastases at bone surfaces. Another example of its potential use would be in the treatment of painful osseous sites.
The alkaline-earth radionuclide radium-223 is useful for the targeting of calcified tissues, e.g., bone and a physiological acceptable solution comprising 223Ra.
The alkaline-earth radionuclide radium-223 is suitable for the use of the nuclide as a cationic species and/or associated to a chelator or another form of a carrier molecule with affinity for calcified tissues. Thus may be combined with a chelator that can be subsequently conjugated to a molecule with affinity for calcified tissues. The effect of the radioisotope to generated by providing a cascade of α-particles on bone surfaces and/or in calcified tumors for the palliation of pain caused by various diseases and/or for the prophylactic use against possible minimal disease to the skeleton, and/or also for the therapeutic treatment of established cancer to the bone. The diseases where the radioisotopes could be used includes, but are not limited to skeletal metastases of prostate-, breast-, kidney- and lung cancer as well as primary bone cancer and also multiple myeloma.